Drug delivery from stents

Abstract

An intravascular stent has a coat comprising a crosslinked amphiphilic polymer and a sparingly water soluble matrix metalloproteinase inhibitor (MMPI). Preferably the polymer is formed from 2-methacryloyloxy-2′-ethyltrimethylammonium phosphate inner salt, C 4-18 alkyl methacrylate and reactive and/or crosslinking monomer and the MMPI is a hydroxamic acid, more preferably batimastat. Preclinical and clinical results are reported, showing good luminal areas and reduced intimal thickening.

1. An intravascular stent comprising a metal body having a coating comprising a polymer and a restenosis inhibiting agent, wherein the restenosis inhibiting agent is a sparingly water soluble matrix metallo-proteinase inhibitor (MMPI) and the polymer in the coating is a cross-linked amphiphilic polymer formed from
 an ethylenically unsaturated zwitterionic monomer comprising a hydrophilic zwitterionic group; 
 an ethylenically unsaturated hydrophobic monomer comprising a pendant hydrophobic group; and 
 an ethylenically unsaturated reactive monomer comprising a pendant reactive group capable of forming intermolecular cross-linkers, 
 
       wherein the zwitterionic monomer has the general formula I:
   YBX  I 
 
       wherein
 B is a straight or branched alkylene, alkyleneoxaalkylene or alkylene oligo-oxaalkylene chain optionally containing one or more fluorine atoms or, if X or Y contains a terminal carbon atom bonded to B, a valence bond; 
 X is a zwitterionic group; and 
 Y is an ethylenically unsaturated polymerisable group selected from 
 
       
         
           
           
               
               
           
         
          CH 2 ═C(R)CH 2 O—, CH 2 ═C(R)CH 2 OC(O)—, CH 2 ═C(R)OC(O)—, CH 2 ═C(R)O—, CH 2 ═C(R)CH 2 OC(O)N(R 1 )—, R 2 OOCCR═CRC(O)O—, RCH═CHC(O)O—, RCH═C(COOR 2 )CH 2 C(O)O—, 
       
       
         
           
           
               
               
           
         
       
       wherein:
 R is hydrogen or a C 1 -C 4  alkyl group; 
 R 1  is hydrogen or a C 1 -C 4  alkyl group or R 1  is —B—X where B and X are as defined above; 
 R 2  is hydrogen or a C 1-4  alkyl group; and 
 K is a group selected from —(CH 2 ) p OC(O)—, —(CH 2 ) p C(O)O—, —(CH 2 ) p OC(O)O—, —(CH 2 ) p NR 3 —, —(CH 2 ) p NR 3 C(O)—, —(CH 2 ) p C(O)NR 3 —, —(CH 2 ) p NR 3 C(O)O—, —(CH 2 ) p OC(O)NR 3 , —(CH 2 ) p NR 3 C(O)NR 3 — (in which the groups R 3  are the same or different), —(CH 2 ) p O—, —(CH 2 ) p SO 3 —, or, optionally in combination with B, a valence bond; 
 p is from 1 to 12; and 
 R 3  is hydrogen or a C 1 -C 4  alkyl group. 
 
     
     
       2. The stent according to  claim 1 , wherein on at least the outer wall of the stent the coating comprises a layer of the amphiphilic polymer in which the MMPI is absorbed. 
     
     
       3. The stent according to  claim 1 , wherein the polymer in the coating, when swollen with water containing pyrene, has hydrophobic domains observable by having a pyrene fluorescence intensity ratio I3:I1 of at least 0.8. 
     
     
       4. The stent according to  claim 1  or  claim 2 , wherein on at least the outer wall of the stent the coating comprises an inner layer of the amphiphilic polymer and, adhered to said inner layer, crystalline MMPI. 
     
     
       5. The stent according to  claim 1 , wherein the pendant hydrophobic group is selected from C 4-24 -alkyl, -alkenyl and -alkynyl groups, any of which may be substituted by one or more fluorine atoms; aryl; C 7-24  aralkyl; oligo (C 3-4  alkoxy) alkyl; and siloxane groups. 
     
     
       6. The stent according to  claim 1 , wherein
 Y is an ethylenically unsaturated polymerisable group selected from CH 2 ═C(R)CH 2 O—, CH 2 ═C(R)CH 2 OC(O)—, CH 2 ═C(R)OC(O)—, CH 2 ═C(R)O—, CH 2 ═C(R)CH 2 OC(O)N(R 1 )—, R 2 OOCCR═CRC(O)O—, RCH═CHC(O)O—, RCH═C(COOR 2 )CH 2 C(O)O—, 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R is hydrogen or a C 1 -C 4  alkyl group; 
 R 1  is hydrogen or a C 1 -C 4  alkyl group or R 1  is —B—X where B and X are as defined above; and 
 R 2  is hydrogen or a C 1-4  alkyl group. 
 
     
     
       7. The stent according to  claim 6 , wherein the cationic group in X is an amine. 
     
     
       8. The stent according to  claim 6 , wherein the anionic group in X is selected from sulphate, sulphonate, phosphate, phosphonate and carboxylate. 
     
     
       9. The stent according to  claim 6 , wherein X is selected from groups of the general formula II, IV and V:
   i) —X 1 —R 4 —N + (R 5 ) 2 —R 6 —V  II 
 
       wherein
 X 1  is a valence bond, —O—, —S— or —NH—; 
 V is a carboxylate, sulphonate or monovalently charged phosphate diester anion; 
 R 4  is a valence bond (together with X 1 ), or alkylene, —C(O)alkylene- or —C(O)NHalkylene; 
 the groups are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms,
 or the groups R 5 , together with the nitrogen to which they are attached, form a heterocyclic ring of 5 to 7 atoms; and 
 
 R 6  is alkylene of 1 to 20 carbon atoms; 
 
       ii) 
       
         
           
           
               
               
           
         
       
       wherein
 X 2  is a valence bond, —O—, —S— or —NH—, 
 R 9  is a valence bond (together with X 2 ), or alkylene, —C(O)alkylene- or —C(O)NHalkylene; and 
 the groups R 8  are the same or different and each is hydrogen or alkyl of 1 to 4 carbon atoms,
 or two of the groups R 8 , together with the nitrogen to which they are attached, form a heterocyclic ring of from 5 to 7 atoms, 
 or the three groups R 8 , together with the nitrogen atom to which they are attached, form a fused ring structure containing from 5 to 7 atoms in each ring; and 
 
 
       iii) 
       
         
           
           
               
               
           
         
       
       wherein
 the moieties X 3  and X 4 , which are the same or different, are —O—, —S—, —NH— or a valence bond, 
 and W +  is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties. 
 
     
     
       10. The stent according to  claim 1 , wherein the hydrophobic monomer has the general formula VII
   Y 1 R 13   VII 
 
       wherein
 Y 1  is selected from 
 
       
         
           
           
               
               
           
         
          CH 2 ═C(R 14 )CH 2 O—, CH 2 ═C(R 14 )CH 2 OC(O)—, CH 2 ═C(R 14 )OC(O)—, CH 2 ═C(R 14 )O—, CH 2 ═C(R 14 )CH 2 OC(O)N(R 15 )—, R 16 OOCCR 14 ═CR 14 C(O)O—, R 14 CH═CHC(O)O—, R 14 CH═C(COOR 16 )CH 2 C(O)O—, 
       
       
         
           
           
               
               
           
         
         wherein:
 R 14  is hydrogen or a C 1 -C 4  alkyl group; 
 R 15  is hydrogen or a C 1 -C 4  alkyl group or R 15  is R 13 ; 
 R 16  is hydrogen or a C 1-4  alkyl group; 
 A 1  is —O— or —NR 15 —; and 
 K 1  a group selected from —(CH 2 ) q OC(O)—, —(CH 2 ) q C(O)O—, —(CH 2 ) q OC(O)O—, —(CH 2 ) q NR 17 , —(CH 2 ) q NR 17 C(O)—, —(CH 2 ) q C(O)NR 17 —, —(CH 2 ) q NR 17 C(O)O—, —(CH 2 ) q OC(O)NR 17 —, —(CH 2 ) q NR 17 C(O)NR 17 — (in which the groups R 17  are the same or different), —(CH 2 ) q O—, —(CH 2 ) q SO 3 —, or a valence bond; 
 q is from 1 to 12; and 
 R 17  is hydrogen or a C 1 -C 4  alkyl group; and 
 
         R 13  is the hydrophobic group. 
       
     
     
       11. The stent according to  claim 10 , wherein R 13  is selected from
 a) C 4-18  alkyl groups; 
 b) C 7-12  aralkyl groups; and 
 c) siloxane groups —(CR 18   2 ) qq (SiR 19   2 )(OSiR 19   2 ) pp R 19  wherein
 each group R 18  is the same or different and is hydrogen, alkyl of 1 to 4 carbon atoms, or aralkyl, 
 each group R 19  is alkyl of 1 to 4 carbon atoms, 
 qq is from 1 to 6 and 
 pp is from 0 to 49. 
 
 
     
     
       12. The stent according to  claim 1 , wherein the reactive monomer has the general formula VIII
   Y 2 B 2 R 20   VIII 
 
       wherein
 B 2  is a straight or branched alkylene, oxaalkylene or oligo-oxaalkylene chain optionally containing one or more fluorine atoms, or B 2  is a valence bond; 
 Y 2  is an ethylenically unsaturated polymerisable group selected from 
 
       
         
           
           
               
               
           
         
          CH 2 ═C(R 21 )CH 2 O—, CH 2 ═C(R 21 )CH 2 OC(O)—, CH 2 ═C(R 21 )OC(O)—, CH 2 ═C(R 21 )O—, CH 2 ═C(R 21 )CH 2 OC(O)N(R 22 )—, R 23 OOCCR 21 ═CR 21 C(O)O—, R 21 CH═CHC(O)O—, R 21 CH═C(COOR 23 )CH 2 C(O)O—, 
       
       
         
           
           
               
               
           
         
         where
 R 21  is hydrogen or C 1 -C 4  alkyl; 
 R 23  is hydrogen, or a C 1-4 -alkyl group; 
 A 2  is —O— or —NR 22 —; 
 R 22  is hydrogen or a C 1 -C 4  alkyl group or R 22  is a group B 2 R 20 ; 
 K is a group selected from —(CH 2 ) k OC(O)—, —(CH 2 ) k C(O)O—, —(CH 2 ) k OC(O)O—, —(CH 2 ) k NR 22 —, —(CH 2 ) k NR 22 C(O)—, —(CH 2 ) k C(O)NR 22 —, —(CH 2 ) k NR 22 C(O)O—, —(CH 2 ) k OC(O)NR 22 —, —(CH 2 ) k NR 22 C(O)NR 22 — (in which the groups R 22  are the same or different), —(CH 2 ) k O—, —(CH 2 ) k SO 3 —, or a valence bond; and 
 k is from 1 to 12; and 
 
         R 20  is a cross-linkable group. 
       
     
     
       13. The stent according to  claim 12 , wherein R 20  is selected from the group consisting of ethylenically and acetylenically unsaturated groups containing radicals; aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C 1-4 -alkoxy groups; hydroxyl; amino; carboxyl; epoxy; —CHOHCH 2 Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; acetoxy; mesylate; carbonyl di(cyclo)alkyl carbodiimidoyl; isocyanate; acetoacetoxy; and oximino. 
     
     
       14. The stent according to  claim 1 , wherein the MMPI is a compound of the general formula XI 
       
         
           
           
               
               
           
         
       
       wherein:
 R 31  represents a hydrogen atom or a C 1-6  alkyl, phenyl, thienyl, substituted phenyl, phenyl(C 1-6 )alkyl, heterocyclyl, (C 1-6 )alkylcarbonyl, phenacyl or substituted phenacyl group; or 
 when a=1, R 31  represents R x , wherein R x  represents a group: 
 
       
         
           
           
               
               
           
         
         R 32  represents a hydrogen atom or a C 1-6  alkyl, C 1-6  alkenyl, phenyl(C 1-6 ) alkyl, cycloalkyl(C 1-6 )alkyl or cycloalkenyl(C 1-6 )alkyl group; 
         R 33  represents an amino acid side chain or a C 1-4  alkyl, benzyl, (C 1-6  alkoxy)benzyl, benzyloxy(C 1-6  alkyl) or benzyloxbenzyl group; 
         R 34  and R 35  independently represent a hydrogen atom or a C 1-4  alkyl group; 
         a is an integer having the value 0, 1 or 2; and 
         A 3  represents a C 1-6  hydrocarbon chain, optionally substituted with one or more C 1-6  alkyl, phenyl or substituted phenyl groups; 
       
       or a salt thereof. 
     
     
       15. The stent according to  claim 14  wherein:
 R 31  represents a hydrogen atom or a C 1-4  alkyl, phenyl, thienyl, benzyl, acetyl or benzoyl group; 
 R 32  represents a C 3-6  alkyl group; 
 R 33  represents a benzyl or 4-(C 1-6 )alkoxyphenyl-methyl or benzyloxybenzyl group; 
 R 34  represents a C 1-4  alkyl group; and 
 R 35  represents a hydrogen atom. 
 
     
     
       16. The stent according to  claim 14 , wherein the MMPI is selected from batimastat [(2R-(1(S*),2R*,3S*))-N4-hydroxy-N1-(2-(methylamino)-2-oxo-1-(phenylmethyl)ethyl)-2-(2-methylpropyl)-3-((thienylthio)methyl)butanediamide] and marimastat. 
     
     
       17. The stent according to  claim 1  or  claim 14 , wherein the MMPI is present in an amount in the range of 1 to 1000 μg. 
     
     
       18. The stent according to  claim 3 , wherein the I3:I1 ratio is about 1. 
     
     
       19. The stent according to  claim 7 , wherein the cationic group in X is a quaternary amine. 
     
     
       20. The stent according to  claim 8 , wherein the anionic group in X is a phosphate diester. 
     
     
       21. The stent according to  claim 9 , wherein:
 for formula II:
 X 1  is —O—; 
 R 4  is C 1 -C 6  alkylene; and 
 R 6  is C 1 -C 6  alkylene; 
 
 for formula IV:
 X 2  is —O—; 
 
 the groups R 8  are methyl; and
 R 9  is C 1 -C 6  alkylene; 
 
 for formula V:
 X 3  and X 4  are —O—; and 
 the group linking the anionic and cationic moieties is a C 1-12 -alkanediyl group. 
 
 
     
     
       22. The stent according to  claim 13 , wherein R 20  is an ethylenically or acetylenically unsaturated group comprising a silane group containing three substituents selected from halogen atoms and C 1-4 -alkoxy groups. 
     
     
       23. The stent according to  claim 22 , wherein R 20  comprises a silane group containing three methoxy groups. 
     
     
       24. The stent according to  claim 17 , wherein the MMPI is present in an amount in the range of 10 to 150 μg.